Enkephalin, a natural opiate receptor agonist in the brain, has been identified [see Hughes et al., Nature, 256, 557 (1975)] as a mixture of two pentapeptides: H-Tyr-Gly-Gly-Phe-Met-OH (methionine-enkephalin) and H-Tyr-Gly-Gly-Phe-Leu-OH (leucine-enkephalin). Both peptides mimic the ability of morphine to block electrically evoked contractions of mouse vas deferens and guinea pig ileum, and both inhibit the stereospecific receptor binding of the opiate antagonist 3H-naloxone in brain homogenates. It has been reported that methionine-enkephalin and leucine-enkephalin, when administered by injection in the brain ventricle in rats, induce a profound analgesia that is fully reversible by naloxone. [See Beluzzi et al., Nature, 260, 625(1976)]. The enkephalins are inactive when administered peripherally, however, and it is believed that the enkephalins are rapidly destroyed by blood enzymes and/or are poorly transported across the bloodbrain barrier.
Various structural modifications of methionine-enkephalin and leucine-enkephalin are described in the literature. For example, H-Tyr-D-Ala-Gly-Phe-Met-NH.sub.2 has been reported by Pert et al., Nature 262, 738(1976) to produce long lasting analgesic after central administration. Bajusz et al., Acta. Biochem. Biophys. Acta. Sci. Hung., 11, 305(1976) report peripheral (i.v.) analgesic activity in rats for H-Tyr-D-Met-Gly-Phe-Pro-NH.sub.2. Fredrickson, Life Sciences, 21, 23(1977) reported H-Tyr-D-Ala-Gly-Phe-D-Met-NH.sub.2 produced analgesic activity in rats when centrally administered. The pentapeptide, H-Tyr-D-Ala-Gly-Phe-D-Leu-OH was shown by Baxter et al., Proc. of the B.P.S. page 456(1977) to exhibit antinociceptive and behavioral effects in both rats and mice after central administration and by Wei et al., Life Sciences, 21, 321(1977) to exhibit peripheral analgesic activity. Romer et al., Nature, 268, 547(1977) has shown that the polypeptide amide ##STR2## possesses potent peripheral analgesic activity and some analgesic activity when given orally at high doses.
The present invention relates to novel synthetic tetrapeptides which produce an analgesic effect in warm-blooded animals upon peripheral administration.